US12454526B2 - Method for producing pyrrole-imidazole (poly)amide - Google Patents

Method for producing pyrrole-imidazole (poly)amide

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US12454526B2
US12454526B2 US17/442,306 US202017442306A US12454526B2 US 12454526 B2 US12454526 B2 US 12454526B2 US 202017442306 A US202017442306 A US 202017442306A US 12454526 B2 US12454526 B2 US 12454526B2
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Takahiko Murata
Shohei Yamamoto
Akira Nishiyama
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Kaneka Corp
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Kaneka Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a method for producing a pyrrole-imidazole (poly)amide by forming an amide bond between a carboxy group binding to pyrrole and an amino group binding to imidazole.
  • N-methylpyrrole-N-methylimidazole (Py-Im)polyamide for example, the compounds represented by the following formulas (101), (102), and (103) are known (Non-Patent Document 1, or the like).
  • the Py-Im polyamides are low molecular weight organic compounds that can cause various sequence-specifically bind to a DNA duplex depending on the combination of pyrrole and imidazole.
  • the Py-Im polyamides are resistant to a nuclease and has nuclear envelope permeability, the Py-Im polyamides are expected to be used in a diagnostic application for identifying DNA sequences and as a molecular probe.
  • the Py-Im polyamides are also expected to be used as a transcriptional regulator that inhibits interaction between a transcription factor and double-stranded DNA.
  • Type 1 is a reaction that forms an amide bond between a carboxy group binding to pyrrole and an amino group binding to another pyrrole
  • type 2 is a reaction that forms an amide bond between a carboxy group binding to imidazole and an amino group binding to another imidazole
  • Type 3 is a reaction that forms an amide bond between a carboxy group binding to imidazole and an amino group binding to pyrrole
  • type 4 is a reaction that forms an amide bond between a carboxy group binding to pyrrole and an amino group binding to imidazole.
  • type 4 reaction is extremely difficult to proceed.
  • an amino bond is formed in high yield by any of the methods: a method in which a carboxylic acid is treated with triphosgen and then reacted with an amino group, and a method in which a carboxylic acid is transformed into an active ester and then reacting with an amino group.
  • a method in which a carboxylic acid is treated with triphosgen and then reacted with an amino group and a method in which a carboxylic acid is transformed into an active ester and then reacting with an amino group.
  • an amide bond is obtained in high yield only when a carboxylic acid is treated with triphosgen and then reacted with an amino group, and an amide bond is obtained in significantly reduced yield in the way that a carboxylic acid is transformed into an active ester and then reacted with an amino group.
  • Non-Patent Document 3 discloses that the pyrrolecarboxylic acid having an amino group protected by a 9-fluorenylmethyloxycarbonyl(Fmoc) group is activated with 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (HBTU) and reacted with aminoimidazole carboxylic acid tert-butyl ester in dimethylformamide (DMF) in the presence of diisopropylethylamine (DIEA). According to the supplementary material, the yield of the amide compound is 79%.
  • HBTU 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate
  • DMF dimethylformamide
  • DIEA diisopropylethylamine
  • the yield is 84% when the amide compound is obtained by subjecting a pyrrolecarboxylic acid having a nitro group at the 4-position to the same condensation reaction condition.
  • Patent Document 1 it is shown that the pyrrolecarboxylic acid having an amino group protected by a tert-butoxycarbonyl(Boc) group is activated with 1-hydroxybenzotriazole (HOBt) and reacted with an aminoimidazole carboxylic acid ethyl ester in DMF in the presence of diisopropylethylamine (DIEA) at 37° C. for 48 hours and the yield is 94%.
  • HOBt 1-hydroxybenzotriazole
  • DIEA diisopropylethylamine
  • Non-Patent Document 3 the amide compound is obtained in a good yield, but it is required to improve the conversion rate more rapidly. It is also disclosed that it takes more than 18 hours to complete the reaction to form an amino bond between the carboxy group bonding to a pyrrole having an amino bond protected by Fmoc group not by Boc group and an amino group bonding to imidazole, in spite of the fact that Fmoc group is better than Boc group in terms of the reaction rate.
  • the reaction to form an amide bond between a carboxy group binding to pyrrole having a nitro group at the 4-position and an amino group binding to imidazole is completed quickly, the nitro group at the 4-position of the pyrrole requires to be transformed into an amino group by a hydrogenation reaction under high pressure condition in order to produce a pyrrole-imidazole (poly)amide from the obtained amide compound.
  • the method cannot be said to be an efficient method for producing a pyrrole-imidazole (poly)amide, since the step to protect the obtained amide compound having an amino group with Fmoc is further needed in some cases.
  • the objective of the present invention is to provide a method to produce a pyrrole-imidazole (poly)amide compound in a high yield and with good reproducibility by rapidly improving the conversion rate even in the case where a nitro group is not introduced at the 4-position of the pyrrole group in the reaction for forming a amide bond between a carboxy group bonding to pyrrole and an amino group bonding to imidazole.
  • the present invention that has solved the above problems is as follows.
  • Ra, Rc, Q 1 , Q 2 , R 1 , R 4 , m and n are the same as described above.
  • Rc, Q 2 , n, and R 4 are the same as described above, to obtain the pyrrolecarboxylic acid derivative represented by the formula (3), and isolating the obtained pyrrolecarboxylic acid derivative represented by the formula (3),
  • R 31 represents a C 1-8 alkyl group
  • * represents a bond
  • R 1 is the same as described above, and Q 11 represents a soluble carrier, a hydroxy group, a C 1-12 alkoxy group optionally having a substituent, a C 2-12 alkenyloxy group optionally having a substituent, a C 6 -12 aryloxy group optionally having a substituent, a C 7-12 aralkyloxy group optionally having a substituent, or an amino group optionally having a substituent.
  • R a1 represents a C 1-8 linear alkyl group
  • R a2 to R a3 independently represents a C 3-10 branched alkyl group, a C 4-8 linear alkyl group, or R a2 and R a3 are connected together to form a C 3-10 saturated ring with the nitrogen atom bound to R a2 and R a3 , wherein the methylene group in the C 3-10 saturated ring may be replaced with an oxygen atom or —CO—.
  • E 1 is any one selected from the formulas (31), (34), (35), and (36)
  • E 2 is any one selected from the formula (31), (33), (34), and (35)
  • R 4 represents a C 1-12 alkyl group
  • R 31 represents a C 1-5 alkyl group
  • * represents a bond.
  • E 1 is any one selected from the formulas (31), (34), (35), or (36).
  • E 2 is any one selected from the formula (31), (33), (34), and (35),
  • R 4 represents a C 1-12 alkyl group,
  • R 31 represents a C 1-5 alkyl group, * represents a bond.
  • [10]A method for forming an amide bond between a carboxy group bound to pyrrole and an amino group bound to imidazole comprising the steps of substituting the OH of the carboxy group bound to pyrrole with a leaving group, and then allowing imidazole having the amino group is to be reacted in the presence of a heterocyclic aromatic compound as a solvent.
  • the amide bond between the carboxy group bound to pyrrole and the amino group bound to imidazole is formed in the presence of a heterocyclic aromatic compound as a solvent, the thermal stability of the pyrrolecarboxylic acid derivative is improved and the conversion rate is rapidly improved; as a result, the production of pyrrole-imidazole (poly)amide can be achieved in high yield and with good reproducibility.
  • FIG. 1 is a graph showing the conversion rates in the reactions of Examples 2 and 3, and Comparative Examples 1 and 2.
  • FIG. 2 is a graph showing the conversion rates in the reactions of Examples 4 and 5, and Comparative Example 1.
  • FIG. 3 is a graph showing the conversion rates in the reactions of Examples 6 and 7, and Comparative Example 1.
  • FIG. 4 is a graph showing the conversion rates in the reactions of Examples 8 to 10, and Comparative Example 1.
  • FIG. 5 is a graph showing the conversion rates in the reactions of Examples 11 and 12.
  • FIG. 6 is a graph showing the conversion rates in the reactions of Example 13 and Comparative Example 1.
  • FIG. 7 is a graph showing the conversion rates in the reactions of Examples 14 and 15, and Comparative Example 1.
  • FIG. 8 is a graph showing the conversion rates in the reactions of Examples 16 to 18.
  • the method for producing a pyrrole-imidazole (poly)amide of the present invention is characterized in that the aminoimidazole carboxylic acid derivative represented by the formula (1) and the pyrrolecarboxylic acid derivative represented by the formula (3) are reacted to form an amide bond in the presence of a heterocyclic aromatic compound as a solvent.
  • a pyrrole-imidazole (poly)amide is produced with a high reproducibility and in a high yield, since the conversion rate is rapidly improved with the improved thermal stability of the raw material.
  • aminoimidazole carboxylic acid derivative used in the production of the pyrrole-imidazole (poly)amide of the present invention is the derivative represented by the following formula (1).
  • Ra is a (poly)-amide-type organic group having 1 or more kinds of a unit selected from the units represented by the formulas (2a), (2b), and (2c) as a constituent unit, wherein a total number of the constituent unit is 1 or more,
  • Q 1 is a carrier, or an amino group optionally having a hydroxy group, an organic group, or a substituent,
  • n 0 or 1
  • R 1 to R 3 independently represent a C 1-12 alkyl group, when the compound represented by the formula (1) has a plurality of units represented by the formula (2a), a plurality of R 2 may be the same as or different from each other,
  • a plurality of R 3 may be the same as or different from each other,
  • Rb represents a C 1-10 alkylene group wherein the alkylene group may be bonded with one or more groups selected from
  • a plurality of Rb may be the same as or different from each other,
  • the constituent unit of the (poly)amide-type organic group represented by Ra is not particularly restricted as long as the unit is the unit represented by the formula (2a), the formula (2b), and the formula (2c). There are no particular restrictions on the order to bond of the units.
  • the content ratio of each unit represented by the formula (2a), the formula (2b), and the formula (2c) constituting the (poly)amide type organic group represented by Ra is not particularly restricted, Ra can be composed of only one of the unit represented by the formula (2a), the formula (2b), or the formula (2c).
  • the ratio of the number of units represented by the formula (2a) in the total constituent units number of the (poly)amide-type organic group represented by Ra is preferably 50% or more, and more preferably 60% or more.
  • the number of constituent units of the (poly)amide-type organic group represented by Ra is preferably 1 or more and 30 or less, more preferably 1 or more and 16 or less.
  • Examples of the C 1-12 alkyl group represented by R 1 to R 3 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and tert-butyl group.
  • a C 1-6 alkyl group is preferable, a C 1-3 alkyl group is more preferable, and a methyl group is further preferable.
  • Examples of the C 1-10 alkylene group represented by Rb include a methylene group, an ethylene group, a propylene group, and a butylene group.
  • the alkylene groups may be linear or branched, and preferably linear.
  • a C 1-8 alkylene group is preferable, and a C 1-5 alkylene group is more preferable.
  • Examples of the amino group that has a substituent and that may be bonded to the C 1-10 alkylene group represented by Rb include the amino groups substituted with one or more selected from C 1-10 alkyl group and a C 6-10 allyl group, such as a methylamino group, an ethylamino group, a dimethylamino group, an ethylmethylamino group, a phenylamino group, a methylphenylamino group, and a diphenylamino group; the amino groups bonded by a protective group, such as an acetylamino group, a tert-butoxycarbonylamino group, a benzyloxycarbonylamino group, a 9-fluorenylmethyloxycarbonylamino group, a 2,2,2-trichloroethoxycarbonylamino group, an aryloxycarbonylamino group, and a trifluoroacetylamino group; an amino group
  • Examples of the amino group having a substituent that may be bonded to a C 1-10 alkylene group represented by Rb preferably include an amino group having a carbamate type protective group, such as a tert-butoxycarbonylamino group and 9-fluorenylmethyloxycarbonylamino group.
  • Examples of the C 1-12 alkoxy group that may be bonded to a C 1-10 alkylene group represented by Rb include a methoxy group, an ethoxy group, a butoxy group, a 2-methoxyethoxy group, and a C 1-6 alkoxy group is preferable.
  • Examples of the C 2-12 alkenyloxy group that may be bonded to a C 1-10 alkylene group represented by Rb include a vinyloxy group, an aryloxy group, and a methallyloxy group, and a C 2-6 alkenyloxy group is preferable.
  • Examples of the C 6-12 aryloxy group that may be bonded to a C 1-10 alkylene group represented by Rb include a phenoxy group, a naphthoxy group, and a biphenyloxy group, and a C 6-10 aryloxy group is preferable.
  • Examples of the C 7-12 aralkyloxy group that may be bonded to a C 1-10 alkylene group represented by Rb include a benzyloxy group and a 1-phenethyloxy group, and a C 7-10 aralkyloxy group is preferable.
  • Examples of the substituent that C 1-12 alkoxy group, C 2-12 alkenyloxy group, C 6-12 allyloxy group, and C 7-12 aralkyloxy group that may be bound to the C 1-10 alkylene group represented by Rb may have include a nitro group; a nitrile group; a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom.
  • Examples of the carriers represented by Q 1 include a solid phase carrier and a soluble carrier.
  • the solid-phase carrier represented by Q 1 is not particularly restricted, and is exemplified by a solid-phase carrier composed of a paper such as a filter paper, a commercially available membrane filter, a glass solid-phase carrier, a silicon solid-phase carrier, a resin solid-phase carrier, a solid-phase carrier containing other polymer compound, a solid-phase carrier containing a metal such as gold, silver, platinum, and iron, and is preferably a resin solid-phase carrier, more preferably PAM Resin manufactured by Sigma-Aldrich Co.
  • polystyrene resin solid-phase carrier such as a carrier to which aminomethylated polystyrene and a monomer are bonded.
  • the size and form of the solid-phase carrier can be appropriately selected those suitable for various operations and detections.
  • Examples of the soluble carriers represented by Q 1 include 3,4,5-tri(n-octadecyloxy)benzyl alcohol, 3,5-di(docosyloxy)benzyl alcohol, 2,4-di(docosyloxy)benzyl alcohol, trityl type compound, 2-[12-(docosyloxy)dodecyloxy]-9-(3-fluorophenyl)-9-bromofluorene.
  • the organic group represented by Q 1 is preferably a C 1-12 organic group and is exemplified by a C 1-12 alkoxy group optionally having a substituent, a C 2-12 alkenyloxy group optionally having a substituent, a C 6-12 aryloxy group optionally having a substituent, and a C 7-12 aralkyloxy group optionally having a substituent.
  • the C 1-12 alkoxy group, C 2-12 alkenyloxy group, C 6-12 aryloxy group, and C 7-12 aralkyloxy group represented by Q 1 may the same as the C 1-12 alkoxy group, a C 2-12 alkenyloxy group, a C 6-12 aryloxy group, and a C 7-12 aralkyloxy groups that may be bonded to the C 1-10 alkylene group represented by Rb, and the preferable range of carbon number is also the same as that of the groups.
  • the substituent that the C 1-12 alkoxy group, C 2-12 alkenyloxy group, C 6-12 aryloxy group, and C 7-12 aralkyloxy group may have is the same as the substituent that the C 1-12 alkoxy group, C 2-12 alkenyloxy group, and C 6-12 aryloxy group that may be bonded to the C 1-10 alkylene group represented by Rb may have, and the substituent that C 7-12 aralkyloxy group may optionally have.
  • the organic group represented by Q 1 are preferably a C 1-12 alkoxy group optionally having a substituent or a C 7-12 aralkyloxy group optionally having a substituent, more preferably a C 1-6 alkoxy group optionally having a substituent or a C 7-10 aralkyloxy group optionally having a substituent, even more preferably a C 1-6 alkoxy group or a C 7-10 aralkyloxy group having a substituent, even more preferably a C 1-6 alkoxy group or a C 7-10 aralkyloxy group having a nitro group as a substituent, and particularly preferably an ethoxy group or a nitrobenzyloxy group.
  • the thermal stability of the aminoimidazole carboxylic acid derivative represented by the formula (1) becomes higher, so that the amide bond can be obtained in a higher yield.
  • the substituent that the amino group represented by Q 1 may have includes a C 1-12 alkyl group, a C 2-12 alkenyl group, a C 7-12 aralkyl group, and a C 6-12 allyl group.
  • a C 1-12 alkylamino group may be bonded to the alkyl group, alkenyl group, aralkyl group, and allyl group.
  • the substituent that the amino group represented by Q 1 may have is preferably a C 1-12 alkyl group bonded by a C 1-12 mono- or dialkylamino group, and the alkyl group is hereinafter referred to as an alkylaminoalkyl group.
  • Examples of the amino group that is represented by Q 1 and that has an alkylaminoalkyl group as a substituent include a (methylaminomethyl)amino group, a (dimethylaminomethyl)amino group, a (2-methylaminoethyl)amino group, a (2-dimethylaminoethyl)amino group, a (3-methylaminopropyl)amino group, and a (3-dimethylaminopropyl)amino group, and the alkyl group to which a dialkylamino group such as a (dimethylaminomethyl)amino group, a (2-dimethylaminoethyl)amino group, and a (3-dimethylaminopropyl)amino group is bonded is preferable, and a (3-dimethylaminopropyl)amino group is more preferable.
  • the amino group that optionally has a substituent and that is represented by Q 1 preferably has one or two substituents, and more preferably has one substituent.
  • aminoimidazole carboxylic acid derivative in the case where m in the formula (1) is 0 is preferably the derivative represented by the following formula (1-1).
  • R 1 is the same as described above, and Q 11 represents a soluble carrier, a hydroxy group, a C 1-12 alkoxy group optionally having a substituent, a C 2-12 alkenyloxy group optionally having a substituent, a C 6-12 aryloxy group optionally having a substituent, a C 7-12 aralkyloxy group optionally having a substituent, or an amino group optionally having a substituent.
  • Examples of the soluble carrier represented by Q 11 include the same soluble carriers represented by Q 1 .
  • the C 1-12 alkoxy group, C 2-12 alkenyloxy group, C 6-12 aryloxy group, and C 7-12 aralkyloxy group represented by Q 11 are the same as the C 1-12 alkoxy group, C 2-12 alkenyloxy group, C 6-12 aryloxy group, and C 7-12 aralkyloxy group that may be bonded to the C 1-10 alkylene group represented by Rb, and the range of the preferable carbon numbers is also the same.
  • the substituent that the C 1-12 alkoxy group, C 2-12 alkenyloxy group, C 6-12 aryloxy group, and C 7-12 aralkyloxy group represented by Q 11 may have is exemplified by the same substituent that the C 1-12 alkoxy group, C 2-12 alkenyloxy group, C 6-12 aryloxy group, and C 7-12 aralkyloxy group that may be bonded to the C 1-10 alkylene group represented by Rb may have.
  • the substituent that the amino group represented by Q 11 may have is exemplified by the same substituents as that the amino group represented by Q 1 may have, and preferable substituent and preferable number of the substituent are also the same.
  • Q 11 is preferably a soluble carrier, a C 7-12 aralkyloxy group optionally having a substituent, and an amino group optionally having a substituent.
  • the C 7-12 aralkyloxy group is more preferably a C 7-10 aralkyloxy group optionally having a substituent, even more preferably a C 7-10 aralkyloxy group having a substituent, even more preferably a C 7-10 aralkyloxy group having a nitro group as a substituent, and particularly preferably a nitrobenzyloxy group.
  • the aminoimidazole carboxylic acid derivative represented by the formula (1) in the production of the pyrrole-imidazole (poly)amide of the present invention may be a free form, a salt with an acid such as hydrochloride, hydrobromide, sulfate, or methanesulfonate, or an alkali metal salt such as lithium salt, sodium salt or potassium salt.
  • the aminoimidazole carboxylic acid derivative represented by the formula (1) may be used in any form of dry crystal, wet crystal, or an extraction solution.
  • the amount of use of the aminoimidazole carboxylic acid derivative represented by the formula (1) in the production of the pyrrole-imidazole (poly)amide of the present invention per 1 mol of the pyrrolecarboxylic acid derivative represented by the formula (3) is, for example, preferably 0.1 mol or more, more preferably 0.5 mol or more, and even more preferably 0.8 mol or more, and for example, preferably 5.0 mol or less, more preferably 2.0 mol or less, and even more preferably 1.5 mol or less.
  • the amount of substance of an aminoimidazole carboxylic acid derivative to 1 mol of a pyrrolecarboxylic acid derivative may be hereinafter referred to as “equivalent (eq)” in some cased.
  • the pyrrolecarboxylic acid derivative used in the production of the pyrrole-imidazole (poly)amide of the present invention is the derivative represented by the following formula (3).
  • Rc is a (poly)amide-type organic group having 1 or more kinds of the unit selected from the units represented by the formulas (4a), (4b), and (4c) as a constituent unit and the total number of the constituent unit is 1 or more,
  • Q 2 is a protective group of an amino group, or a group represented by the formulas (5a), (5b), (5c) or (5d),
  • n 0 or 1
  • R 4 to R 8 each independently represents a C 1-12 alkyl group
  • a plurality of R 5 may be the same as or different from each other,
  • a plurality of R 6 may be the same as or different from each other,
  • Rd represents a C 1-10 alkylene group wherein the alkylene group may be bonded with one or more groups selected from an amino group having a substituent, a C 1-12 alkoxy group optionally having a substituent, a C 2-12 alkenyloxy group optionally having a substituent, and a C 6-12 aryloxy group optionally having a substituent, and a C 7-12 aralkyloxy group optionally having a substituent,
  • a plurality of Rd may be the same as or different from each other,
  • Re represents a C 1-10 alkyl group wherein the alkyl group may be bonded with one or more groups selected from an amino group having a substituent, a C 1-12 alkoxy group optionally having a substituent, a C 2-12 alkenyloxy group optionally having a substituent, a C 6-12 aryloxy group optionally having a substituent, and a C 7-12 aralkyloxy group optionally having a substituent,
  • the constituent unit of the (poly)amide-type organic group represented by Rc is not particularly restricted as long as the constituent unit is the unit represented by the formula (4a), the formula (4b), and the formula (4c), and the bonding order of each unit is not particularly restricted.
  • the content ratio of each unit represented by the formula (4a), the formula (4b), and the formula (4c) constituting the (poly)amide type organic group represented by Rc is not particularly limited.
  • Rc may be constituted only of any one of the units represented by the formula (4a), the formula (4b), or the formula (4c).
  • the ratio of the number of the units represented by the formula (4a) is preferably 50% or more, and more preferably 60% or more, in the total number of the constituent units of (poly)amide-type organic group represented by Ra.
  • the number of constituent units of the (poly)amide-type organic group represented by Rc is preferably 1 or more and 30 or less, and more preferably 1 or more and 16 or less.
  • Examples of the protective group of the amino group represented by Q 2 include a C 1-15 substituted or unsubstituted alkyloxycarbonyl group such as a tert-butyloxycarbonyl group, a methoxycarbonyl group, or a 9-fluorenylmethoxycarbonyl group; a C 7-12 substituted or unsubstituted aralkyloxycarbonyl group such as a benzyloxycarbonyl group and a p-methoxybenzyloxycarbonyl group; a C 2-12 substituted or unsubstituted acyl group such as an acetyl group and a benzoyl group.
  • a C 1-15 substituted or unsubstituted alkyloxycarbonyl group such as a tert-butyloxycarbonyl group, a methoxycarbonyl group, or a 9-fluorenylmethoxycarbonyl group
  • the protective group of the amino group represented by Q 2 is preferably a C 1-15 substituted or unsubstituted alkyloxycarbonyl group, more preferably a tert-butyloxycarbonyl group and a 9-fluorenylmethoxycarbonyl group.
  • Q 2 is preferably the protective group of amino group or the groups represented by the formula (5a), the formula (5b), the formula (5c) or the formula (5d), and is more preferably the protective group of the amino group.
  • Examples of the C 1-12 alkyl group represented by R 4 to R 8 include the same as the C 1-12 alkyl group represented by R 1 to R 3 , and the preferred group is also the same.
  • Examples of the leaving group represented by E include a halogen atom, an oxime residue, and an —OR X group.
  • R X represents a nitrogen atom-containing complex such as a triazolidinone ring group, a triazole ring group, a succinimide ring group, and a dimethoxytriazyl ring group; an aryl halide group; a carboxylic acid ester group; a sulfonic acid ester group; an acyl group; the groups may optionally have a substituent.
  • the leaving group is preferably an oxime residue, or —OR X group, and more preferably the following formulas (31) to (36). When the leaving group represented by E is the formulas (31) to (36), the thermal stability of the pyrrolecarboxylic acid derivative is further improved, and then the conversion rate is rapidly improved, therefore, an amide bond can be formed in a high yield.
  • R 31 represents a C 1-5 alkyl group, and * represents a bond.
  • Examples of the C 1-5 alkyl group represented by R 31 include the C 1-5 alkyl group among the C 1-12 alkyl group represented by R 1 to R 3 .
  • R 31 is preferably a C 1-3 alkyl group, and more preferably an ethyl group.
  • the leaving group represented by E is more preferably the formula (31), the formula (32), the formula (33), the formula (35), or the formula (36), even more preferably the formula (32), the formula (33) or the formula (35), and particularly preferably the formula (35).
  • the leaving group represented by E is the formula (32), the formula (33), or the formula (35)
  • an amide bond can be formed in a higher yield.
  • the leaving group represented by E is the formula (33) or the formula (35)
  • the reactivity is enhanced, and an amide bond can be formed in a high yield and in a short reaction time.
  • Examples of the C 1-10 alkylene represented by Rd include the same as the C 1-10 alkylene group represented by Rb, and the preferable range of carbon atoms is also the same.
  • Examples of the amino group having a substituent, C 1-12 alkoxy group optionally having a substituent, C 2-12 alkenyloxy group optionally having a substituent, C 6-12 aryloxy group optionally having a substituent, and C 7-12 aralkyloxy group optionally having a substituent that may be bonded to the C 1-10 alkylene group represented by Rd include the same as the amino group having a substituent, C 1-12 alkoxy group optionally having a substituent, C 2-12 alkenyloxy group optionally having a substituent, C 6-12 aryloxy group optionally having a substituent, and C 7-12 aralkyloxy group optionally having a substituent that may be bonded to the C 1-10 alkylene represented by Rb, and the range of the preferred groups is also the same.
  • Examples of the C 1-10 alkyl group represented by Re include the C 1-10 alkyl group among the C 1-12 alkyl groups represented by R 1 to R 3 .
  • Re is preferably a C 1-8 alkyl group, and more preferably a C 1-5 alkyl group.
  • Examples of the amino group having a substituent, C 1-12 alkoxy group optionally having a substituent, C 2-12 alkenyloxy group optionally having a substituent, C 6-12 aryloxy group optionally having a substituent, and C 7-12 aralkyloxy group optionally having a substituent that may be bonded to the C 1-10 alkylene group represented by Re include the same as the amino group having a substituent, C 1-12 alkoxy group optionally having a substituent, C 2-12 alkenyloxy group optionally having a substituent, C 6-12 aryloxy group optionally having a substituent, and C 7-12 aralkyloxy group optionally having a substituent that may be bonded to the C 1-10 alkylene group represented by Rb, and the range of the preferred groups is also the same.
  • the pyrrolecarboxylic acid derivative represented by the formula (3) is produced by reacting a pyrrolecarboxylic acid represented by the following formula (3)′ with the reagents such as 1-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), cyano (hydroxyimino)ethyl acetate (Oxyma), and pentafluorophenol (HOPFP) and a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
  • the reagents such as 1-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), 1-hydroxy-7-azabenzotriazole (HO
  • Rc, Q 2 , n, and R 4 are the same as described above.
  • the pyrrolecarboxylic acid derivative represented by the formula (3) in the production of the pyrrole-imidazole (poly)amide of the present invention is preferably in an isolated state by removing the condensing agent contained in the step of producing the pyrrolecarboxylic acid derivative represented by the formula (3).
  • the method for isolating the pyrrolecarboxylic acid derivative represented by the formula (3) is not particularly restricted, examples thereof include extraction, washing, and crystallization, and at least washing or crystallization may be preferably included.
  • the pyrrolecarboxylic acid derivative in the case where n in the formula (3) is 0 is preferably the pyrrolecarboxylic acid derivative compound represented by the following formula (3-1-1) or the formula (3-1-2).
  • R 4 is the same as the above, E 1 is any one selected from the formulas (31), (34), (35), and (36), and E 2 is any one selected from the formulas (31), (33), (34), and (35), and * represents a bond.
  • the pyrrolecarboxylic acid derivative in the case where n in the formula (3) is 0 is also preferably a solid pyrrolecarboxylic acid derivative compound represented by the following formula (3-2-1) or the formula (3-2-2).
  • E 1 , E 2 and R 4 are the same as described above.
  • E 1 is preferably represented by the formula (35).
  • E 1 is represented by the formula (35)
  • an amide bond can be formed in a higher yield.
  • an amide bond can be formed in a higher yield and in a shorter reaction time.
  • E 2 is preferably any one selected from the formula (33) or the formula (35), more preferably the formula (35).
  • E 2 is any one selected from the formula (33) or the formula (35)
  • an amide bond can be formed in a higher yield.
  • E 2 is represented by the formula (35)
  • the reactivity is further increased, and an amide bond can be formed in a higher yield and in a shorter reaction time.
  • the method for precipitating the solid of the pyrrolecarboxylic acid derivative compound represented by the formulas (3-2-1) and (3-2-2) is not particularly restricted.
  • the following methods (a) to (d) can be exemplified.
  • the methods (a) to (d) may be used in combination to precipitate the solid. Further, a seed solid may be added to precipitate a solid.
  • the reaction time can be shortened and a quality of the obtained pyrrole-imidazole (poly)amide also become improved.
  • a tertiary amine may be added in order to further accelerate the reaction.
  • tertiary amines examples include trimethylamine, triethylamine, tripropylamine, tributylamine, trypentylamine, trihexylamine, triheptylamine, trioctylamine, tridodecylamine, dodecyldimethylamine, hexyldibutylamine, diisopropylbutylamine, diisopropylethylamine, dimethylethylamine, dicyclohexylmethylamine, N,N-dimethylbenzylamine, N-methylpyrrolidin, N,N-dimethyl-4-aminopyridine, quinuclidine, N-methylmorpholin, 1,4-diazabicyclo[2,2,2]octane, and 1,8-diazabicyclo[5,4,0]-7-undecene.
  • the tertiary amines may be used alone or in combination of two or more.
  • the tertiary amine is preferably triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylbenzylamine, N,N-dimethyl-4-aminopyridine, or N-methylmorpholine, and more preferably the amine represented by the following formula (a).
  • R a1 represents a C 1-8 linear alkyl group
  • R a2 to R a3 independently represent a C 3-10 branched alkyl group, a C 4-8 linear alkyl group, or a C 3-10 saturated ring formed by R a2 and R a3 connected together to form the ring with the nitrogen atom bound to R a2 or R a3 , and the methylene group in the C 3-10 saturated ring may be replaced with an oxygen atom or —CO—.
  • Examples of the C 1-8 linear alkyl group represented by R a1 include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group.
  • Examples of the C 3-10 branched alkyl group represented by R a2 to R a3 include an isopropyl group, an isobutyl group, a tert-butyl group, an isopentyl group, a sec-pentyl group, a 1-ethylpropyl group, neopentyl group, and tert-pentyl group.
  • the branched chain alkyl group represented by R a2 to R a3 is preferably a C 3-6 branched chain alkyl group.
  • Examples of the C 4-8 linear alkyl group represented by R a2 to R a3 include an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group.
  • the linear alkyl group represented by R a2 to R a3 is preferably a C 4-6 linear alkyl group.
  • Examples of the C 3-10 saturated ring formed by R a2 and R a3 connected together with the nitrogen atom bound to R a2 and R a3 include the followings.
  • the C 3-10 saturated ring formed by R a2 and R a3 connected together with the nitrogen atom bound to R a2 and R a3 is preferably a C 3-6 saturated ring. Further, one number of the methylene group in the saturated ring is preferably replaced with an oxygen atom or —CO—, and more preferably one number of the methylene group in the saturated ring is replaced with an oxygen atom.
  • the tertiary amine is more preferably diisopropylethylamine, tributylamine, or N-methylmorpholine.
  • the amount of use of the tertiary amine used in the production of the pyrrole-imidazole (poly)amide of the present invention per 1 mol of the pyrrolecarboxylic acid derivative represented by the formula (3) is, for example, preferably 0.5 mol or more, more preferably 1.0 mol or more, even more preferably 2.0 mol or more, or even more preferably 3.0 mol or more, and for example, preferably 100 mol or less, more preferably 50 mol or less, and even more preferably 10.0 mol or less.
  • the amount of substance of the tertiary amine per 1 mol of the pyrrolecarboxylic acid derivative may be hereinafter referred to as “equivalent (eq)” in some cases.
  • the reaction between the aminoimidazole carboxylic acid derivative and the pyrrolecarboxylic acid derivative in the present invention is carried out in the presence of a heterocyclic aromatic compound as a solvent.
  • heterocyclic aromatic compound mentioned examples include a pyrrole such as pyrrole, 2-methylpyrrole, and 3-methylpyrrole; a pyridine such as 2-methylpyridine, 4-methylpyridine, 2,3-dimethylpyridine, 2,4-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 3,4-dimethylpyridine, and 3,5-dimethylpyridine; and a quinoline such as quinoline.
  • the heterocyclic aromatic compounds may be used alone or in combination of two or more, and the mixing ratio is not particularly restricted.
  • the aromatic ring structure in the heterocyclic aromatic compound and the aromatic ring structure in the pyrrolecarboxylic acid derivative cause a n-n interaction, and further, a hydrogen bond is formed between the heteroatom such as a nitrogen atom and an oxygen atom in the heterocyclic aromatic compound and the amino group in the aminoimidazole carboxylic acid derivative.
  • the conversion rate is rapidly improved and the yield becomes high in the binding reaction between the aminoimidazole carboxylic acid derivative and the pyrrolecarboxylic acid derivative.
  • a solvent other than the heterocyclic aromatic compound may be used in combination.
  • the solvent other than the heterocyclic aromatic compound include a saturated hydrocarbon solvent such as n-pentane, n-hexane, cyclohexane, and methylcyclohexane; an aromatic hydrocarbon solvent such as toluene and xylene; a halogen solvent such as chloroform, dichloromethane, chlorobenzene, and dichlorobenzene; an alcohol solvent such as methanol, ethanol, and isopropanol; a ketone solvent such as acetone, methyl ethyl ketone, and acetophenone; an ether solvent such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane; an ester solvent such as ethyl acetate, tert-
  • the amount of use of the solvent other than the heterocyclic aromatic compound to 100 parts by mass of the heterocyclic aromatic compound as a solvent is, for example, 150 parts by mass or less, preferably 140 parts by mass or less, and more preferably 120 parts by mass or less.
  • the melting point of the compound is, for example, preferably 0° C. or lower, and more preferably ⁇ 10° C. or lower.
  • the heterocyclic aromatic compound mentioned above is preferably a pyridine compound such as pyridine, 2-methylpyridine and 4-methylpyridine, and more preferably pyridine.
  • the amount of use of the heterocyclic aromatic compound to 1 part by mass of the pyrrolecarboxylic acid derivative represented by the formula (3) is, for example, preferably 1 part by mass or more, more preferably 1.5 parts by mass or more, even more preferably 2 parts by mass or more, and for example, preferably 500 parts by mass or less, more preferably 400 parts by mass or less, and even more preferably 300 parts by mass or less.
  • the conversion rate to the pyrrole-imidazole (poly)-amide and the yield of the pyrrole-imidazole (poly)amide become improved, and the reproducibility also becomes high.
  • the reaction between the aminoimidazole carboxylic acid derivative represented by the formula (1) and the pyrrolecarboxylic acid derivative represented by the formula (3) is, in short, the synthetic reaction of the pyrrole-imidazole (poly)amide by allowing the imidazole having an amino group to act on the compound in which the OH of the carboxy group bonding to pyrrole is replaced with the leaving group in the presence of the heterocyclic aromatic compound as a solvent to form an amide bond between the carboxy group bonding to pyrrole and the amino group bonding to imidazole.
  • the temperature at which the aminoimidazole carboxylic acid derivative and the pyrrolecarboxylic acid derivative are reacted is not particularly restricted.
  • the temperature is, for example, 0° C. or higher, preferably 10° C. or higher, more preferably 15° C. or higher, and for example, 100° C. or lower, preferably 80° C. or lower, more preferably 50° C. or lower.
  • the time for reacting the aminoimidazole carboxylic acid derivative with the pyrrolecarboxylic acid derivative may be appropriately set according to the structure of the aminoimidazole carboxylic acid derivative and the pyrrolecarboxylic acid derivative, the type of the heterocyclic aromatic compound, and the reaction temperature.
  • the time for reaction is, for example, 0.5 hours or more, preferably 1 hour or more, more preferably 5 hours or more, and for example, 96 hours or less, preferably 84 hours or less, more preferably 72 hours or less.
  • the order of addition of the aminoimidazole carboxylic acid derivative, the pyrrolecarboxylic acid derivative, the heterocyclic aromatic compound, and the tertiary amine used as necessary in synthesizing the pyrrole-imidazole (poly)amide is not particularly restricted, and for example, the tertiary amine may be added to the solution to which the aminoimidazole carboxylic acid derivative and the heterocyclic aromatic compound have already been added, and then the pyrrolecarboxylic acid derivative may be added.
  • the pyrrole-imidazole (poly)amidepyrrole synthesized by reacting the pyrrolecarboxylic acid derivative of the present invention with the aminoimidazole carboxylic acid derivative, that is, by reacting the carboxy group bonding to pyrrole and the amino group bonding to imidazole to form an amide bond is represented by the following formula (6).
  • Ra, Rc, Q 1 , Q 2 , R 1 , R 4 , m, and n are the same as described above.
  • the pyrrole-imidazole (poly)amide obtained in the synthesis may be isolated and purified as needed.
  • a common separation method can be used preferably in combination, and the method may be, for example, extraction, concentration, crystallization and column chromatography.
  • N, N-Dimethylformamide (hereinafter referred to as DMF; 100 mL), H 2 O (17 mL) and Cs 2 CO 3 (7.2 g, 22.0 mmol) were added to 4-[(tert-butoxycarbonyl)amino]-1-methylimidazole-2-carboxylic acid (10.0 g, 41.5 mmol), and the mixture was stirred at 40° C. for 30 minutes. Subsequently, 4-nitrobenzyl bromide (10.2 g, 47.3 mmol) was added, and the mixture was stirred for 29 hours. Then, the reaction solution was added to H 2 O (500 mL) in an ice bath, and the mixture was stirred for 30 minutes.
  • DMF N, N-Dimethylformamide
  • Example 1-1 Production of Boc-Py-OOBt, Referred to as Pyrrolecarboxylic Acid Derivative Represented by Formula (3-B)
  • Example 1-2 Production of Boc-Py-OSu, Referred to as Pyrrolecarboxylic Acid Derivative Represented by Formula (3-D)
  • Example 1-4 Production of Boc-Py-OPFP, Referred to as Pyrrolecarboxylic Acid Derivative Represented by Formula (3-F)
  • DMF (0.2 mL), HOBt-H 2 O (55.1 mg, 0.36 mmol) and dicyclocarbodiimide (hereinafter referred to as DCC; 74.3 mg, 0.36 mmol) were added to 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid (72.1 mg, 0.3 mmol), and the solution was stirred for 24 hours. Then, the by-product of dicyclohexylurea (hereinafter referred to as DCU) was removed by filtration.
  • DCC dicyclocarbodiimide
  • Example 2 Production of ethyl 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylate; Amidation Reaction in Pyridine Solvent Using Isolated Boc-Py-OBt
  • the solution was washed with 5% aqueous sodium carbonate solution (10 mL) three times, H 2 O (10 mL) one time and 5% aqueous potassium hydrogen sulfate solution (10 mL) one time, dried over sodium sulfate, filtrated, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (152.6 mg, 0.23 mmol, pure content: 90.8 mg, yield: 77.3%).
  • Example 3 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid 4-nitrobenzyl ester; Amidation Reaction in Pyridine Solvent, Using Isolated Boc-Py-OBt
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate, filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (151.9 mg, 0.18 mmol, pure content: 90.4 mg, yield: 60.4%).
  • a production method in which the conversion rate becomes 50% or more within 5 hours after the start of a reaction is preferable because of the satisfying conversion rate.
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate, filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (101.1 mg, 0.26 mmol, yield: 86.1%).
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate, filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (100.9 mg, 0.26 mmol, pure content: 90.4 mg, yield: 85.9%).
  • Example 6 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidation Reaction in Pyridine/DMF Mixed Solvent Using Isolated Boc-Py-O(Oxyma)
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate, filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (78.4 mg, 0.20 mmol, yield: 66.7%).
  • Example 7 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidaiton Reaction in Picoline Solvent Using Isolated Boc-Py-O(Oxyma)
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate, filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (80.4 mg, 0.21 mmol, yield: 68.4%).
  • Example 8 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Boc-Py-O(Oxyma) and TEA
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate, filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target as a concentrate (93.8 mg, 0.18 mmol, yield: 79.9%).
  • Example 9 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Boc-Py-O(Oxyma) and TBA
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time, 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate, filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (107.0 mg, 0.27 mmol, yield: 91.1%).
  • Example 10 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Boc-Py-O(Oxyma) and NMM
  • NMM N-methylmorpholine
  • 4-amino-1-methylimidazole-2-carboxylic acid ethyl ester hydrochloride 74.0 mg, 0.36 mmol
  • isolated solid Boc-Py-O(Oxyma) 109.3 mg, 0.3 mmol was added, and the mixture was stirred at 37° C. for 6 hours.
  • the reaction solution was cooled to 20° C., and dichloromethane (5 mL) was added.
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate and filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (109.6 mg, 0.28 mmol, yield: 93.3%).
  • Example 11 Production of 4-[(9-fluorenylmethoxycarbonyl)amino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Fmoc-Py-OAt
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate and filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (139.2 mg, 0.27 mmol, yield: 90.3%).
  • Example 12 Production of 4-[(9-fluorenylmethoxycarbonyl)amino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Fmoc-Py-O(Oxyma)
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate and filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (106.2 mg, 0.21 mmol, yield: 84.8%).
  • Example 13 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid 4-nitrobenzyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Boc-Py-O(Oxyma)
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate and filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (112.2 mg, 0.18 mmol, yield: 75.0%).
  • Example 14 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid ethyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Boc-Py-O(Oxyma)
  • the solution was washed with 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate and filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (97.8 mg, 0.25 mmol, yield: 83.3%).
  • Example 15 Production of 4-[(tert-butoxy)carbonylamino]-1-methylpyrrole-2-(4-carboxamide-1-methylimidazole)-2-carboxylic acid 4-nitrobenzyl ester; Amidation Reaction in Pyridine Solvent Using Isolated Boc-Py-O(Oxyma)
  • the solution was washed with 5% aqueous sodium carbonate solution (20 mL) three times, H 2 O (20 mL) one time and 5% aqueous potassium hydrogen sulfate solution (20 mL) one time, dried over sodium sulfate and filtrated, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the solid target product (2.4 g, 4.2 mmol, yield: 75.6%).
  • the solution was washed 5% aqueous sodium carbonate solution (5 mL) three times, H 2 O (5 mL) one time and 5% aqueous potassium hydrogen sulfate solution (5 mL) one time, dried over sodium sulfate and filtered, and the obtained solution was concentrated under reduced pressure at 30° C. to obtain the target product as a concentrate (116.3 mg, 0.25 mmol, yield: 83.8%).
  • H-Im-Py-OEt.HCl referred to as aminoimidazole-pyrrolecarboxylic acid derivative represented by the formula (1-C); 65.6 mg, 0.2 mmol.
  • isolated solid Boc-Py-O(Oxyma) 87.4 mg, 0.24 mmol was added, and the mixture was stirred at 37° C. for 2.5 hours.
  • H-Im-Im-OEt.HCl referred to as aminoimidazole-imidazolecarboxylic acid derivative represented by the formula (1-D); 65.8 mg, 0.2 mmol.
  • isolated solid Boc-Py-O(Oxyma) 87.4 mg, 0.24 mmol was added, and the mixture was stirred at 37° C. for 2.5 hours.
  • TFA trifluoroacetic acid
  • NMP N-methylpyrrolidone
  • An NMP solution of Boc-Im-OOBt (referred to as aminoimidazole carboxylic acid derivative represented by the formula (1-F-2); 309 mg, 0.8 mmol) and DIPEA (155 mg, 1.2 mmol) was separately prepared, added to a reaction vessel filled with the resin, and shaken at 25° C. for 18.5 hours. After the reaction solution was filtrated, the residue was washed with NMP (8 mL) three times, and then dichloromethane (8 mL) three times.
  • the obtained resin bound by pyrrole-imidazole (poly)amide was dried under reduced pressure, 1 mL of 3-(dimethylamino)-1-propylamine (hereinafter referred to as Dp) was added, and the mixture was stirred at 55° C. for 21 hours. After the PAM resin was removed by filtration, the filtrate was concentrated under reduced pressure at 45° C. to remove Dp in order to obtain the target product as a concentrate (19 mg, 0.036 mmol, yield: 94.9%).
  • Fmoc-( ⁇ -Ala)-Wang resin (referred to as Wang resin bound by N-(9-fluorenylmethyloxycarbonyl)- ⁇ -alanine represented by the formula (1-G-1); 227 mg, 0.66 mmol/g, 0.15 mmol) was swollen with dichloromethane (5 mL) for 2 hours, the solution was filtrated and the residue was washed with 5 mL of NMP, and this procedure was repeated three times. Then, 8 mL of a 20% piperidine/NMP solution was added for de-Fmoc reaction for 90 minutes.

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